This invention relates to benzamine derivatives which are selective for dopamine D-2 receptors, to methods of preparing such compounds, to methods of utilizing them as imaging agents, and to novel compounds useful as intermediates in the preparation of such D-2 receptors.
Dopamine is a neural transmitter, a chemical that is used to send messages from one brain cell to another. Neurotransmitters bind to special receptor proteins in the membrane of nerve cells, like a key in a lock, triggering a chemical reaction within the cell. Imbalances in dopamine production and use have been implicated in a variety of mental disorders. Insufficient production of dopamine, for example, causes Parkinson's disease which affects more than a million people in the United States. Its symptoms include tremors and rigidity of limbs, and treatment involves replacing the dopamine through drugs or by implanting dopamine-secreting tissues into the brain. An excess production of dopamine, in contrast, is thought to be one of the major factors in the development of schizophrenia, which is characterized by disordered thought, hallucinations and inappropriate emotional responses. An estimated three million people in the United States suffer from schizophrenia, including forty percent of all patients in mental hospitals. Anti-psychotic drugs such as chlorpromazine and haloperidol, which halt hallucinations and delusions, are used to treat schizophrenia because they bind to the D-2 dopamine receptors, preventing the excess dopamine from overstimulating them.
For the treatment of a wide variety of different nervous and mental diseases such as schizophrenia and Parkinson's Disease, it is desirable to be able to monitor the effectiveness of drugs and substances which affect brain chemistry. For instance, it is highly desirable to be able to gauge the biochemical effects of drugs administered for blocking the patient's dopamine receptors. If too little of the drug is administered, the desired blockade does not occur, and if too much of the drug is administered, there can be severe side effects.
New and powerful imaging methods which enable one to assess the living brain in vivo and thereby monitor the effectiveness of drugs and substances that affect brain chemistry have recently been developed. Methods such as positron emission tomography (PET) and single photon emission tomography (SPECT) involve the administration to a patient of radioactive tracer substances comprising a ligand that binds to presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays which are emitted from the positrons or photons emitted from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control, to determine the degree of drug response. Further treatment of the patient with drugs is based upon the comparisons made.
It is generally accepted that there are two subtypes of dopamine receptors, designated as D-1 and D-2 receptors. Recent reports have suggested that these two subtypes of receptors exhibit opposite biochemical effects: D-1 agonists stimulate adenyl cyclase activity, while D-2 agonists inhibit the enzyme activity. It is clear that these receptor subtypes influence each other, and yet they display separate and distinct functions on body physiology and biochemistry. Monitoring of D-2 receptors in a patient is important for assessing the dopaminergic system and ultimately assisting patient management.
A variety of substituted benzamide derivatives possessing antipsychotic and antiemetic properties have been reported. (Ogren, S. O., Hall, H., Kohler, C., et al. Eur. J. Pharmacol. 1984, 102,459; Florvail, L., Ogren, S. J. Med. Chem. 1982, 25, 1280; de Paul is, T. , Kumar, Y., Johansson, L., et al. J. Med. Chem. 1985, 28, 1263; Hall, H., Wedel, I. Acta Pharmacol. Toxicol. 1986, 58, 363; Hogberg, T., Ramsby, S., Ogren, S., Norinder, U. Acta Pharm. Suec. 1987, 24, 289). The pharmacological effects of these agents are assumed to be induced by blocking the CNS D-2 dopamine receptor. In this series of benzamide derivatives, agents with an N-ethyl-pyrrolidinyl-methyl amine group appear to be the most attractive antagonists, showing the best selectivity and the highest affinity for the CNS D-2 dopamine receptor. Raclopride (Kohler, C., Ogren, S., Gawell, L. Biochem. Pharmacol. 1985, 34, 2251) and eticlopride (Kohler, C., Hall, H., Gawell, L. Eur. J. Pharmacol. 1986, 120, 217; Hakan, H., Kohler, C., Gawell, L. Eur. J. Pharmacol. 1985, 111, 191) are two excellent examples which show specific D-2 antagonistic activity, with high affinity in rat striatum tissue preparations and low nonspecific binding. See Table 1. Radioactive benzamides are not only potentially useful as imaging agents (labeled with .sup.123 I, T.sub.1/2 =13 h, gamma ray energy=159 keV), but are also very valuable as pharmacological tools for probing the D-2 dopamine receptor under in vitro and in vivo conditions (labeled with .sup.125 I, T.sub.1/2 =60 d gamma energy=30-65 keV). Several iodinated benzamide derivatives, iodosulpiride (Martres, M. -P., Sales, N., BoutSenet, M. -L., Schwartz, J. -C. Eur. J. Pharmacol. 1985, 118, 211), iodoazidoclebopride (Neumeyer, J. L., Guan, J. -H., Niznik, H. B., Dumbrille-Ross, A., Seeman, P., Padmanabhan, S., Elmaleh, D. R. J. Med. Chem. 1985, 28, 405), iodopride (Janowsky, A., de Paulis, T., Clanton, J. A., Smith, H. E., Ebert, M. H., .Kessler, R. M. Eur. J. pharmacol. 1988, 150, 203) and IBZM (Kung, H. F., Billings, J. J., Guo, Y.-Z., Xu, X., Mach, R. H., Blau, M., Ackerhalt, R. A. Nucl. Med. Biol. 1988, 15, 195; Kung, H. F., Billings, J. J., Guo, Y.-Z., Mach, R. H. Nucl. Med. Biol. 1988, 15, 203; Kung, H. F., Kasliwal, R., Pan, S., Kung, M.-P., Mach, R. H., Guo, Y.-Z. J. Med. Chem. 1988, 31, 1039) have been reported as showing very high affinity and selectivity to the D-2 dopamine receptor in the same striatal membrane preparation.
TABLE 1 ______________________________________ Chemical Structures and In Vitro Binding Constants of Benzamides ##STR1## Compound R.sub.1 R.sub.2 R.sub.3 K.sub.d (nM) ______________________________________ Iodosulpiride H SO.sub.2 NH.sub.2 H 1.5 Raclopride OH Cl Cl 1.1 Eticlopride OH C.sub.2 H.sub.5 Cl 0.17 IBZM OH I H 0.43 BZM OH H H 31.1 Iodopride H I H 3.0* Iodoazidoclebopride -- -- -- 14 ______________________________________ *IC.sub.50 against [H.sup.3 }spiperone binding of rat striatal tissue preparation.
Imaging studies of CNS D-2 dopamine receptor in humans with [.sup.11 C]raclopride (labeled at the N-ethyl group), in conjunction with positron emission tomography (PET), have been reported. (Farde, L., Ehrin, E., Eriksson, L., et al. Proc. Natl. Acad. Sci. (USA) 1985, 82, 3863; Haldin, C., Stone-Elander, S., Farde, L., et al. J. Labeled Compd. Radiopharm. 1986, 23, 1408; Ehrin, E., Farde, L., de Paulis, T., et al. Int. J. Appl. Rad. Isot. 1985, 36, 269; Farde, L., Hall, H., Ehrin, E., et al. Science 1986, 231, 258; Farde, L., Hall, H., Pauli, S., et al. Psychopharmacol. 1988, 94, 471; Farde, L., Wiessel, F. A., Hall, H., Halldin, C., Stone-Elander, S., Sedvall, G. Arch. Gen. Psychiat. 1987, 44, 671). A high ratio of specific striatal to nonspecific cerebellar binding in living human brain was observed. Using an equilibrium model and Scatchard plots, the affinity constant (K.sub.d =7.1 nM, B.sub.max =15 pmole/ml) in living human brain was measured by PET. (Farde, L., Hall, H., Pauli, S., et al. Psychopharmacol. 1988, 94, 471; Farde, L. , Wiesel, F. A. , Hall, H., Halldin, C., Stone-Elander, S., Sedvall, G. Arch. Gen. Psychiat. 1987, 44, 671). The values for the dopamine D-2 receptor density were comparable to those determined earlier using a different imaging agent, N-methylspiperone (K.sub.d =0.097 nM, B.sub.ma x=16.6 pmole/g). (Wagner, H. N., Burns, H. D., Dannals, R. J., et al. Science 1983, 221, 1264; Wong, D. F., Wagner, H. N., Dannals, R. J., et al. Science 1984, 226, 1393; Wong, D., Gjedde, A., Wagner, H. N. J. Cereb. Blood. Flow. Metab. 1986, 6, 137). Planar imaging studies in humans with S-[.sup.123 I]IBZM (S--the active isomer, R-- the inactive isomer), immediately after intravenous injection, demonstrate that this agent, as expected, displayed high concentration in basal ganglia of the brain. Single photon emission computed tomography (SPECT) imaging of normal human brain at 1 hour postinjection displayed a pattern which clearly indicates the highly specific uptake in the basal ganglia of the brain. (Kung, H. F., unpublished data).
Several other potential SPECT and PET dopamine receptor imaging agents, based on radiolabeled spirperone or its derivatives, have been reported. (Saji, H., Nakatzuka, I., Shiba, K. Life Sci. 1987, 41, 1999; Nakatzuka, I., Saji, H., Shiba, K., et al. Life Sci. 1987, 41, 1989; Shine, C.-Y., Bai, L.-Q., Teng, R.-T., et al. J. Nucl. Med. 1987, 28, 1164; Chi, D. Y., Kilbourn, M. R., Katzenellenbogen, J. A., et al. Appl. Radiat. Isot. 1986, 12, 1173; Kiesewetter, D. O., Eckelman, W. C., Cohen, R. W., et al. Appl. Radiat. Isot. 1986, 12, 1181; Welch, M. J., Chi, D., Mathias, C. J., et al. Nucl. Med. Biol. 1986, 12, 523; Satyamurthy, N., Bida, G. T., Barrio, J. R., et al. Nucl. Med. Biol. 1986, 13, 617; Coenen, H. H., Laufer, P., Stoecklin, G., et al. Life Sci. 987, 40(1), 81; Arnett, C. D., Fowler, J. S., Wolf, A. P. Life Sci. 1985, 36, 1359; Owen, F., Crawley, J., Cross, M., et al. Br. Pshychopharm. Monogr. 1985, 216, 227; Crawley, J. C. W., Crow, T. J., Johnstone, E. C., et al. Nucl. Med. Comm. 1986, 7, 599). Preliminary studies of an iodinated 2'-iodo-spiperone (2'-ISP) indicate that the spiperone analog displays excellent D-2 specificity (Kd=0.25 nM, rat striatum) and in vivo stability as compared to the 4-iodo-spiperone (Gundlach, A. L., Largent, B. L., Synder, S. H. Life Sci. 984, 35, 1981) reported earlier. In vitro binding data for 2'-ISP appears to show a higher nonspecific binding (40%) than that observed with [.sup.125 I]IBZM (5%). (Kung, H. F., Kasliwal, R., Pan, S., Kung, M.-P., Mach, R. H., Guo, Y.-Z. J. Med. Chem. 1988, 31, 1039). In addition, several new .sup.18 F labeled compounds including spiperone itself, N-methyl spiperone (Arnett, C. D., Fowler, J. S., Wolf, A. P. Life Sci. 1985, 36, 1359), N-fluoroalkyl-spiperones (Welch, M. J., Chi, D., Mathias, C. J., et al. Nucl. Med. Biol. 1986, 12, 523; Satyamurthy, N., Bida, G. T., Barrio, J. R., et al. Nucl. Med. Biol. 1986, 13, 617; Coenen, H. H., Laufer, P., Stoecklin, G., et al. Life Sci. 1987, 40(1), 81; Arnett, C. D., Fowler, J. S., Wolf, A. P. Life Sci. 1985, 36, 1359) and [.sup.77 Br]4-bromospiperone have been reported. (Owen, F., Crawley, J., Cross, M., et al. Br. Pshychopharm. Monogr. 1985, 216, 227; Crawley, J. C. W., Crow, T. J., Johnstone, E. C., et al. Nucl. Med. Comm. 1986, 7, 599). The structures of several of the above-mentioned compounds are illustrated in Table 2.
TABLE 2 ______________________________________ Chemical Structures of Spiperone-Based Dopamine Receptors ##STR2## Compound R X Y ______________________________________ Spiperone H H H N-methyl spiperone CH.sub.3 H H N-fluoroethyl spiperone CH.sub.2 CH.sub.2 F H H N-fluoropropyl spiperone CH.sub.2).sub.3 F H H 2'-iodo-spiperone H I H 4-iodo-spiperone H H I 4-bromo-spiperone H H Br ______________________________________
Recently, several patents describing the synthesis and pharmacological studies of bicyclic benzamide analogs have been reported. (Lednicer, D., Sun, J. H. Eur. Pat. Appl. EP 147044 A2, 3 Jul. 1985; Florvail, L., Johansson, L., Kumar, Y., DePaulis, T., Ogren, S. Brit. UK Pat. Appl. GB 2176785 A1, 7 Jan. 1987). Of particular interest is the dihydrobenzofuran series, the bromo and chloro derivatives have displayed high pharmacological potential and good receptor affinity in an In vitro binding assay. Still, there is a need for new. iodinated D-2 dopamine receptor imaging agents with higher receptor affintiy (longer retention time in the brain for data accumulation and less in vivo metabolism).